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MelanomaPhase 1/2NCT03480152

Messenger RNA (mRNA)-Based, Personalized Cancer Vaccine Against Neoantigens Expressed by the Autologous Cancer

A Phase 1/2 study testing National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine in people with Melanoma and Colon Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

Background: Exome sequencing can identify certain gene mutations in a person's tumor. This can then be used to create cancer treatments. In this study, researchers will make a treatment called a messenger ribonucleic acid (mRNA) vaccine. The vaccine might cause certain tumors to shrink. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Melanoma, Colon Cancer, Gastrointestinal Cancer
What is being tested?
National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
1 siteUnited States
Study dates
18 May 2018to 5 Nov 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Measurable (per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria), metastatic melanoma, gastrointestinal, or genitourinary cancer with at least one lesion that is resectable. Only patients with metastatic gastrointestinal cancer will be eligible for enrollment on the Phase I portion of the study. Patients with metastatic melanoma, gastrointestinal, or genitourinary cancer will be eligible for enrollment on the Phase II portion of the study.
  • Confirmation of diagnosis of metastatic cancer by the National Cancer Institute (NCI) Laboratory of Pathology.
  • Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.
  • Prior therapy with at least one first-line standard of care treatment or second-line treatment of proven effectiveness. Patients must have progressive disease after prior treatment. Prior first-or second-line treatments would include the following:
  • Patients with metastatic melanoma: Receipt of a checkpoint inhibitor as first-line therapy
  • Patients with metastatic melanoma with an activating mutation of KIT: Receipt of Imatinib
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  • Patients with a BRAF V600 activating mutation: Receipt of appropriate targeted therapy
  • Patients with metastatic gastrointestinal cancer: Receipt of up to two forms of approved first- and/or second-line chemotherapy regimens
  • Patients with metastatic genitourinary cancers: Receipt of a first- or second-line therapy appropriate for their histologic subtype
  • Age greater than or equal to 18 years and less than or equal to 70 years.
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
  • Serology
  • Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)
  • Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative.
  • Hematology
  • Absolute neutrophil count (ANC) > 1000/mm(3) without the support of growth factors.
  • White blood cell (WBC) greater than or equal to 3000/mm(3)
  • Platelet count greater than or equal to 100.000/mm(3)
  • Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.
  • Chemistry
  • Serum Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) less than or equal to 5.0 times upper limit of normal (ULN)
  • Serum creatinine <1.5 times ULN or measured creatinine clearance (calculated using Cockcroft-Gault formula) > 40 ml/min
  • Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin < 3.0 mg/dl.
  • More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the immunization regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo).
  • Ability of subject to understand and the willingness to sign a written informed consent document.
  • Subjects must be co-enrolled on protocol 03-C-0277.

Who cannot join

  • Pregnant or breastfeeding women who do not consent to stop breast-feeding while on study treatment and for 30 days after the use of the investigational vaccine where pregnancy is confirmed by a positive, rising human chorionic gonadotropin (hCG) laboratory test.
  • Women of child-bearing potential, defined as all women capable of becoming pregnant, unless they agree to use an appropriate method of contraception during dosing and for 120 days after the last dose (i.e., final vaccine). Effective contraception methods include a combination of any two of the following (unless method is abstinence or sterilization, in which only one method is required):
  • Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%). In case of use of oral contraception, women should have been stable on the same pill for a minimum of 6 months before taking study treatment.
  • Placement of an intrauterine device or intrauterine system.
  • Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
  • Total abstinence
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  • Female sterilization at least eight weeks before taking study treatment.
  • Male sterilization (at least six months prior to screening).
  • Sexually active males must use a condom during intercourse during dosing and for 120 days after the last dose (i.e., final vaccine), and should not father a child in this period.
  • Any systemic steroid therapy or other form of immunosuppressive therapy within 7 days of the first dose of the vaccine. A physiologic dose of systemic corticosteroids may be approved. Inhaled or topical steroids, and less than or equal to 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
  • Active systemic infections requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses of the cardiovascular, respiratory, or immune system.
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
  • Concurrent opportunistic infections (the experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities).
  • Any vaccinations four weeks prior to the first vaccination cycle or live vaccines at any time during the study.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: A Phase I/II Trial to Evaluate the Safety and Immunogenicity of a Messenger RNA (mRNA)-Based, Personalized Cancer Vaccine Against Neoantigens Expressed by the Autologous Cancer

Background:

Exome sequencing can identify certain gene mutations in a person's tumor. This can then be used to create cancer treatments. In this study, researchers will make a treatment called a messenger ribonucleic acid (mRNA) vaccine. The vaccine might cause certain tumors to shrink.

Read more

Objective:

To see if the mRNA vaccine is safe and can cause metastatic melanoma or epithelial tumors to shrink.

Eligibility:

People 18-70 years old with metastatic melanoma or epithelial cancer

Design:

Participants will be screened under protocol 99-C-0128.

Participants will provide samples under protocol 03-C-0277:

Participants will provide a piece of their tumor from a previous surgery or biopsy.

Participants will have leukapheresis: Blood is removed through a needle in one arm and circulated through a machine that takes out the white blood cells. The blood is then returned through a needle in the other arm.

Participants will have many tests:

Scans and x-rays

Heart and lung function tests

Blood and urine tests

Participants will receive the mRNA vaccine every 2 weeks for up to 8 weeks. They will get the vaccine as an injection into the upper arm or thigh. They may receive a second course of vaccines if the study doctor determines it is needed.

Participants will have follow-up visits approximately 2 weeks after their final vaccine, then 1 month later, then every 1-2 months for the first year, and then once a year for up to 5 years. Each visit may take up to 2 days and include:

Physical exam

Blood tests

Scans

Leukapheresis at the first visit

Read the detailed description

Background:

  • Therapeutic vaccination against cancer has proven very challenging with little clinical benefit.
  • Vaccines against non-viral tumors have mainly targeted differentiation antigens, cancer testis antigens, and overexpressed antigens. However, negative selection in the thymus against these normal non-mutated antigens severely limits the ability to generate high avidity anti-cancer T-cells. Such depletion can impair their antitumor activity and limit tumor elimination.
  • The National Cancer Institute Surgery Branch (NCI-SB) has developed a pipeline for the identification of immunogenic T-cell epitopes derived from neoantigens.
  • In recent studies, we identified the neoantigens recognized by tumor-infiltrating lymphocytes (TIL) that mediated regression in patients with metastatic melanoma. Using whole exome sequencing of a resected metastatic nodule followed by high throughput immunologic screening, we were able to demonstrate that tumor regressions were associated with the recognition by the administered TIL of unique somatic mutations that occurred in the cancer.
  • We also found that TIL from 29 of 32 patients with a wide variety of metastatic gastrointestinal cancers contained lymphocytes that recognized unique mutations presented in that patient's cancer.
  • We, therefore, aim to use this pipeline to identify immunogenic neoantigens and to predict for neoantigens binding the patient human leukocyte antigen (HLA) molecules from melanoma or epithelial cancer patients and to use these epitopes for a personalized therapeutic messenger ribonucleic acid (mRNA) vaccine.

Objectives

Primary objectives:

  • Determine the clinical response rate in patients with metastatic melanoma, gastrointestinal or genitourinary cancers who receive NCI-4650
  • Determine the safety of NCI-4650 in patients with metastatic melanoma, gastrointestinal or genitourinary cancers

Eligibility

  • Age greater than or equal to 18 years and less than or equal to 70 years
  • Evaluable metastatic melanoma, gastrointestinal, or genitourinary cancers refractory to standard of care treatment
  • Metastatic cancer lesions suitable for surgical resection to perform whole exome sequencing and preparation of TIL

Design:

  • Patients with metastatic cancer will undergo surgical resection of tumor followed by exome and RNA sequencing to identify expressed mutations. This will be conducted under the NCI-SB cell harvest protocol 03-C-0277. (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).
  • Immunogenic neoantigens will be identified from TIL by high throughput immunologic screening using long peptides and tandem minigenes covering all mutated epitopes.
  • Up to 15 predicted neoantigens will be selected based on exome and RNA sequencing and their binding affinity to the patient HLA molecules.
  • The mRNA vaccine will be manufactured and supplied as Current Good Manufacturing Practice (cGMP) product by ModernaTX, Inc.
  • The patient will be vaccinated with mRNA containing epitopes from immunogenic neoantigens, predicted neoantigens and mutations in tumor suppressor or driver genes.
  • The mRNA vaccine will be administered intramuscularly (IM) for four cycles every two weeks. A patient may receive a second course for a total of eight cycles given.
  • Blood samples will be taken every two weeks (during the vaccination period) and at each follow-up visit, and patients will be monitored for the quantity and quality of circulating neoantigen-specific T-cells.
Being tested
National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine
Keywords
Metastatic Cancer, Immunotherapy, Tumor Regression, Cancer Vaccine, Gene Therapy
Medical subject headings
Melanoma, Colonic Neoplasms, Gastrointestinal Neoplasms, Urogenital Neoplasms, Liver Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer VaccineBiological

    Patients will receive a messenger ribonucleic acid (mRNA)-based vaccine intramuscularly at two-week intervals for four cycles (one course of treatment). Patients may be vaccinated with a second and final course of treatment using the same vaccine dose. The second course may start approximately four weeks (plus or minus 2 weeks) from the last vaccine dose of the first course.

Study groups in NCT03480152
Study groupRoleWhat they receive
1/Phase - Escalating doses of mRNA vaccineExperimentalEscalating doses of messenger ribonucleic acid (mRNA) vaccine
Receives: Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine
2/Phase II -MTD of mRNA vaccine established in Phase IExperimentalMaximum tolerated dose (MTD) of messenger ribonucleic acid (mRNA) vaccine established in Phase I
Receives: Biological: National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Who Had a Clinical Response (Complete Response + Partial Response) to Treatment (Objective Tumor Regression)

    Clinical response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

    Measured: up to 12 months

  2. Number of Non-Serious Adverse Events Probably Related to Treatment

    Here is the number of non-serious adverse events probably related to treatment assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

    Measured: During treatment and up to 30 days after the first follow- up evaluation (at the second follow-up evaluation)

Secondary outcomes (1)

  1. Number of Participants With an Increase in the Quantity and Quality of Circulating Antigen-specific T Cells

    Participants blood samples were assessed by fluorescence-activated cell sorting (FACS), enzyme-linked immune absorbent (ELISA)-spot and human soluble cluster of differentiation 137 (CD137) (4-1BB) upregulation assays. Differences of 2-3 fold in these assays over the baseline measures are indicative of true biologic difference.

    Measured: Approximately 2 weeks after last vaccine

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Mar 2018
  2. Study start18 May 2018
  3. Primary completion25 Jun 2019
  4. Study completion5 Nov 2019

Why it stopped: slow accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03480152
Sponsor's protocol ID
180074
Other IDs
18-C-0074
Status last verified
May 2020
First submitted
27 Mar 2018
Last updated
2 Jun 2020
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Klein L, Hinterberger M, Wirnsberger G, Kyewski B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat Rev Immunol. 2009 Dec;9(12):833-44. doi: 10.1038/nri2669.

    PubMed 19935803

  • Bos R, Marquardt KL, Cheung J, Sherman LA. Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment. Oncoimmunology. 2012 Nov 1;1(8):1239-1247. doi: 10.4161/onci.21285.

    PubMed 23243587

  • Abramson J, Giraud M, Benoist C, Mathis D. Aire's partners in the molecular control of immunological tolerance. Cell. 2010 Jan 8;140(1):123-35. doi: 10.1016/j.cell.2009.12.030.

    PubMed 20085707

  • Cafri G, Gartner JJ, Zaks T, Hopson K, Levin N, Paria BC, Parkhurst MR, Yossef R, Lowery FJ, Jafferji MS, Prickett TD, Goff SL, McGowan CT, Seitter S, Shindorf ML, Parikh A, Chatani PD, Robbins PF, Rosenberg SA. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020 Nov 2;130(11):5976-5988. doi: 10.1172/JCI134915.

    PubMed 33016924

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing National Cancer Institute (NCI)-4650, a messenger ribonucleic acid (mRNA)-based, Personalized Cancer Vaccine in people with Melanoma and Colon Cancer, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Apr 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants Who Had a Clinical Response (Complete Response + Partial Response) to Treatment (Objective Tumor Regression) (time frame: up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03480152, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2020.

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